4-Tertiary-amino-2,6-diaminopyridine 1-oxides

ABSTRACT

A series of 2,6-diamino-4-tertiary-amino-pyridine 1-oxides is disclosed. Substituents in the 4-position include diethylamino, pyrrolidinyl, piperidino, morpholino, thiomorpholino, and N-methyl-piperazino. Novel oxadiazolones such as 5-amino-7-(1-piperidinyl)-2H-[1,2,4]-oxadiazolo[2,3-a]pyridine-2-one which are useful in the preparation of the pyridine 1-oxides are also disclosed. The compounds of this invention lower blood pressure in normotensive and hypertensive mammals and are particularly useful in the treatment of hypertensive conditions in mammals. 2,6-Diamino-4-(1-piperidinyl)pyridine 1-oxide is a representative embodiment of the invention.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of co-pending application Ser. No.638,473 filed Dec. 8, 1975 now U.S. Pat. No. 4,021,562.

BACKGROUND OF THE INVENTION

The present invention is concerned with4-tertiary-amino-2,6-diaminopyridine 1-oxides and pharmaceuticallyacceptable acid addition salts thereof. It is further concerned with aprocess for making the foregoing compounds, intermediates useful in thepreparation thereof and to an antihypertensive therapeutic process.

References illustrating the state of the art relating to the compoundsof the instant invention are British Pat. No. 1,355,461 and U.S. Pat.Nos. 3,329,569 and 3,382,248.

U.S. Pat. No. 3,329,569 relates to a series of2,6-diamino-4-substituted-pyridines and corresponding N-oxides whereinsubstitution in the 4-position includes alkoxy and phenoxy. The patentteaches that administration of the compounds to normotensive andhypertensive dogs results in a significant drop in blood pressure.

U.S. Pat. No. 3,382,248 relates to6-amino-1,2-dihydro-1-hydroxy-2-iminopyrimidines such as6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine. Thecompounds are reported to be useful as antihypertensive agents,antifertility agents, anti-inflammatory agents and as central nervoussystem stimulants.

SUMMARY OF THE INVENTION

This invention pertains to novel 4-tertiary-amino-2,6-diaminopyridine1-oxides and pharmaceutically acceptable acid addition salts thereofcharacterized by Formula I ##STR1## wherein R is selected from the groupof radicals consisting of diethylamino, pyrrolidino, piperidino,morpholino, thiomorpholino, and N-methylpiperazino.

The term "pharmaceutically acceptable acid addition salt" used hereindenotes a salt form of a 4-tertiary-amino-2,6-diaminopyridine 1-oxidebase of Formula I obtained by combination with inorganic or organicacids. Suitable acids which may be used to form pharmacologicallyacceptable acid addition salts are those acids which are relativelynontoxic in their anionic form such as sulfuric, hydrochloric,phosphoric, hydrobromic, hydroiodic, sulfamic, methanesulfonic,benzenesulfonic, p-toluenesulfonic, acetic, lactic, succinic, maleic,mucic, tartaric, citric, gluconic, benzoic, cinnamic, isethionic,fumaric, and related acids. Preparation of acid addition salts isaccomplished in conventional fashion by treating the base of Formula Iin a suitable organic solvent such as ethanol, benzene, ether,chloroform, etc., with at least one molecular equivalent of the acid.Isolation of the salt is carried out by conventional techniques. Forinstance, the acidified solution is concentrated or the productprecipitated by the addition of a co-solvent such as ether, isopropylether, ethyl acetate and the like in which the salt has limitedsolubility. Both mono- and diacid-addition salts are considered withinthe purview of the invention.

The 4-tertiary-amino-2,6-diaminopyridine 1-oxides of Formula I areobtained by reacting a compound of Formula II ##STR2## wherein X ishalogen with a R-H secondary amine wherein R is as defined above.Displacement of the halogen atom (preferably chlorine or bromine) by theR-H amine is accompanied by aminolysis of the ethoxycarbonylamino groupsin the 2,6-position at the "C-N" bond to provide the compounds ofFormula I. In addition to Formula I compounds, mono- and bis-ureidescorresponding to Formula III and IV, respectively, wherein R is asdefined above are obtained as a result of interaction of the R-H aminewith the 2,6-ethoxycarbonylamino groups. The compounds of Formulas IIIand IV are useful as intermediates in the preparation of the compoundsof Formula I ##STR3##

If desired, the product of Formula I can be isolated from the reactionmixture containing the compounds of Formula III and IV by conventionalmethods such as crystallization of the concentrated reaction mixture orchromatographic separation thereof. However, the preferred procedure isto convert the Formula III and IV compounds obtained followingdisplacement of the halogen to the desired Formula I product byhydrolyzing the concentrated reaction mixture with an alkali base suchas potassium hydroxide.

The displacement of the halogen atom of the starting material of FormulaII with the secondary R-H amine is carried out in the temperature rangeof 100°-200° C. and preferably in the range of 125°-175° C. In view ofcompeting reactions mentioned above which result in compounds of FormulaIII and IV along with the desired compounds of Formula I at least threemolecular equivalents of the R-H amine to the Formula II chloro compoundis employed. Preferably, sufficient R-H amine is used in order that ahomogenous mixture is obtained when the reactants are mixed and heated.

Treating the mono-ureides of Formula III with dilute acid results inhydrolysis of the ureide and cyclization to provide novel oxidiazolonesof Formula V wherein R is as defined above. ##STR4##

Compounds of Formula V are readily converted to compounds of Formula Iby alkaline hydrolysis and accordingly are valuable intermediates.

Illustrative of compounds of the invention prepared according to theforegoing methods are:

2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide,

2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide,

2,6-diamino-4-(pyrrolidino)pyridine 1-oxide,

2,6-diamino-4-(diethylamino)pyridine 1-oxide,

2,6-diamino-4-(thiomorpholino)pyridine 1-oxide,

2,6-diamino-4-(N-methylpiperazino)pyridine 1-oxide,

which are obtained by reaction of4-chloro-2,6-bis-(ethoxycarbonylamino)pyridine 1-oxide with therespective amines: piperidine, morpholine, pyrrolidine, diethylamine,thiomorpholine and N-methylpiperazine, respectively.

The 4-tertiary-amino-2,6-diaminopyridine 1-oxides of Formula I,pharmaceutically acid addition salts thereof, and the compounds ofFormula V have hypotensive and antihypertensive properties and are,therefore, useful in treating conditions in mammals responsive toadministration of such agents. They are orally and parenterally active.Standard pharmacological tests can be employed to demonstrate thehypotensive and antihypertensive utility of the instant compounds. Forexample, intravenous administration of2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide to the anesthetizednormotensive dog in a dosage range of from 0.1 to 10 mg./kg. body weightprovides a dose related reduction in blood pressure. In the spontaneoushypertensive rat, oral administration of2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide at a dose of 2.5 mg./kg.body weight provides a reduction in blood pressure of 50 mm. Hg. Thedesirable antihypertensive effects are obtained with no adversetoxicity.

A feature of the instant invention includes a method of reducing bloodpressure in a mammal in need thereof comprising systemic administrationto the mammal a substantially nontoxic, effective dose to reduce bloodpressur of from 0.1 to 10 mg./kg. body weight of a compound of Formula Ior a pharmaceutically acceptable salt thereof or a compound of FormulaV. The term systemic administration as used herein includes both oraland parenteral routes such as intramuscular, intravenous,intraperitoneal and subcutaneous. The dosage will vary to some extentwith the form of administration and the particular compound chosen.Generally, the compound is administered at a dosage substantially lessthan the dose of the compound which is thought to be effective.Thereafter, in conformity with accepted therapeutic methods, the dosageis increased by small increments until the desired antihypertensive orhypotensive effect is reached.

The 4-substituted-2,6-diaminopyridine 1-oxides of Formula I andpharmaceutically acceptable salts thereof can be formulated according toconventional pharmaceutical practice to provide pharmaceuticalcompositions of unit dosage form. Such compositions include solid orliquid dosage forms such as tablets, capsules, powders, pills, granules,emulsions, suspensions, syrups, elixirs, suppositories, sterile aqueousor vegetable oil dispersion and the like. For most purposes, unit dosageforms containing from 5 to 500 mg. of one of the compounds of Formula Iwith a pharmaceutically acceptable carrier are suitable.

Powders are prepared by comminuting the active ingredient to a suitablefine size and mixing with a similarly comminuted diluent. The diluentcan be edible carbohydrate material such as starch. Sweetening andflavoring agents can be combined with the powders as desired.

The tablets are made from a powder mixture, by granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the active ingredient in a suitable comminuted formwith a diluent or base such as starch, lactose, dicalcium phosphate,calcium sulfate, and the like. The powder mixture can be granulated bywetting with a binder such as syrup, gelatin solution, methylcellulosesolution or acacia mucilage and forcing through a screen. As analternative to wet granulation, the powder mixture can be slugged (i.e.,run through a tablet machine) and the resulting large tablets brokendown into granules. The granules are further lubricated to preventsticking in the tablet forming dyes by means of addition of stearicacid, a stearate salt, talc, or mineral oil. The lubricated mixture isthen compressed into tablets. If desired, the tablet can be providedwith a protective coating consisting of a sealing coat of shellac, acoating of sugar and methyl cellulose, and a polish coating of carnubawax.

Capsules are produced by preparing a powder mixture as hereinabovedescribed and filling into formed gelatin capsules. Lubricants, such astalc, magnesium stearate and calcium stearate, may be added to thepowder mixture before the filling operation.

For oral administration, unit dosage form such as syrups and elixirswherein each teaspoon full of composition contains a predeterminedamount of active ingredient are useful. A syrup is prepared bydispersing the active ingredient in a suitably flavored aqueous sucrosesolution. Similarly, an elixir is prepared utilizing anaqueous-alcoholic vehicle.

In preparing parenteral unit dosage forms for administration, a measuredamount of active ingredient is placed in a vial and the vial and itscontents are sterilized and sealed.

The compounds which constitute this invention and their methods ofpreparation will appear more fully from a consideration of the followingexamples and apended claims which are given for the purpose ofillustration only and are not to be construed as limiting the inventionin sphere or in scope.

With reference to the "NMR" data given below, tetramethylsilane wasemployed as the internal reference peak and chemical shift delta valuesare in parts per million. The following multiplicity notations areemployed: s = singlet, d = doublet, t = triplet, m = multiplet (centerlisted), q = quintuplet, bs = broad singlet.

EXAMPLE 1 2,6-Diamino-4-(4-morpholinyl)pyridine 1-oxide HydrochlorideHydrate

(a) A mixture of 4-chloro-2,6-bis(ethoxycarbonylamino)-pyridine (148.0g., 0.51 mole), 296 ml. of acetic acid, and 250 ml. of 40% peraceticacid is stirred at 70° C. for 3 hr. The hot solution is poured into 4liters of ice water providing a solid which is collected, washed withwater and air dried. Crystallization of the dried solid from 3 liters of95% ethanol affords 118.0 g. (76% yield), of4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide having a meltingpoint of 146°-149° C. Recrystallization of this material from 95%ethanol affords analytically pure4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide, m.p.149.5°-150.5° C.

Analysis. Calcd. for C₁₁ H₁₄ CLN₃ O₅ (percent): C, 43.50; H, 4.65; N,13.84; Cl, 11.67. Found (percent): C, 43.61; H, 4.55; N, 13.77; Cl,11.76. NMR (CDCl₃): 1.31 (t, 6H, 7.0 Hz); 4.28 (q, 4H, 7.0 Hz);

7.84 (s, 2H); 8.80 (bs, 2H).

(b) A mixture of 4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide(10.0 g., 0.03 mole) and 60 ml. of morpholine is refluxed with stirringunder a nitrogen atmosphere for a period of 24 hrs. and concentrated todryness. The residual material thus obtained is taken up in 200 ml. ofabsolute ethanol and 24.0 g. (0.36 mole) of 85% potassium hydroxide.After stirring at reflux temperature for a period of 16 hr., 200 ml. ofabsolute ethanol is added and reflux continued for an additional periodof 30 hr. Concentration of the basic solution to dryness provides aresidue which on stirring with water affords 4.4 g. (69% yield) of2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide as the free base, m.p.315°-325° C. (dec.). The free base is taken up in absolute ethanol andacidified with ethanolic hydrogen chloride. Addition of ethyl acetate tothe acidified ethanolic solution and cooling affords the product whichis collected and crystallized from absolute ethanol to provide 2.8 g. ofanalytically pure 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxidehydrochloride hydrate, m.p. 203.5°-206.5° C. (dec.) (corr.).

Analysis. Calcd. for C₉ H₁₄ N₄ O₂.HCl.H₂ O (percent): C, 40.84; H, 6.47;N, 21.16. Found (percent): C, 41.10; H, 6.67; N, 21.40. NMR (DMSO-d₆):3.23 (m, 4H); 3.68 (m, 4H); 5.67 (s, 2H); 7.22 (bs, 4H).

EXAMPLE 2 2,6-Diamino-4-(1-piperidinyl)pyridine 1-oxide

(a) A mixture of 4-chloro-2,6-bis-(ethoxycarbonylamino)pyridine 1-oxide(10.0 g., 0.03 mole) obtained according to the procedure of Example 1(a)and 60 ml. of piperidine is heated in a sealed tube at 135° C. for aperiod of 48 hr. The reaction mixture is concentrated to dryness and theresidual material taken up in a mixture of chloroform and 10% aqueoussodium carbonate. After separating the organic and aqueous fractions,the aqueous layer is washed with chloroform, the chloroform fractionscombined and dried over magnesium sulfate. The dried chloroform extractis concentrated to a volume of approximately 100 ml., cooled andfiltered to afford 0.52 g., (8% yield) of2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide, m.p. 249°-265° C. (dec.).

(b). The chloroform filtrate from Example 2(a) is concentrated andchromatographed on an alumina column employing chloroform as the eluant.Concentration of the chloroform effluant affords a residual materialwhich crystallized from isopropyl ether provides 2.2 g. (17% yield) of4-(1-piperidinyl)-2,6-bis[(1-piperidinylcarbonyl)amino]-pyridine1-oxide, m.p. 125°-137° C. Further crystallization of this material fromethyl acetate affords analytically pure4-(1-piperidinyl)-2,6-bis[(1-piperidinylcarbonyl)amino]pyridine 1-oxide,m.p. 136° C. to a cloudy melt clearing at 159.5° C.

Analysis. Calcd. for C₂₂ H₃₄ N₆ O₃ (percent): C, 61.37;

H, 7.96; N, 19.52. Found (percent): C, 61.05; H, 8.01; N, 19.44.

NMR (CDCl₃): 1.64 (m, 18H); 3.53 (m, 12H); 7.50 (s, 2H);

9.66 (bs, 2H).

(c). The chloroform-eluted chromatographic column of Example 2(b) isfurther eluted with a solvent combination comprised of 9:1chloroform-methanol. Concentration of the chloroform-methanol effluentprovides 6.5 g. of solid material which crystallized from 95% ethanoland ethyl acetate affords analytically pure2-amino-4-(1-piperidinyl)-6-[(1-piperidinylcarbonyl)amino]pyridine1-oxide, m.p. 248.5°-249.5° C. (dec.).

Analysis. Calcd. for C₁₆ H₂₅ N₅ O₂ (percent): C, 60.17;

H, 7.89; N, 21.92. Found (percent): C, 59.99; H, 7.90; N, 21.93.

NMR (CDCl₃): 1.63 (m, 12H); 3.26 (m, 4H); 3.54 (m, 4H);

5.56 (bs, 2H); 5.75 (d, 1H, 3.0 Hz); 7.32 (d, 1H, 3.0 Hz); 9.90 (bs,1H).

(d). 2-Amino-4-(1-piperidinyl)-6-[(1-piperidinylcarbonyl)-amino]pyridine1-oxide (5.37 g., 0.017 mole) is dissolved in 100 ml. of 3N hydrochloricacid. After stirring the acid mixture for 0.5 hr. at room temperature,the mixture is cooled and neutralized with 50% sodium hydroxideaffording a solid. The solid is collected, washed with water and airdried to provide 3.7 g. of crude oxadiazolone product, m.p. 283° C.(dec.). Further purification is carried out by dissolving the crudeproduct in 300 ml. of methanol and treating the solution with activatedcharcoal. Concentration of the methanol solution to a volume ofapproximately 125 ml. and cooling affords 2.9 g. (73% yield) of5-amino-7-(1-piperidinyl)-2H-[1,2,4]-oxadiazolo[2,3-a]-pyridin-2-one,m.p. 246.5° C. (dec.) (corr.).

Analysis. Calcd. for C₁₁ H₁₄ N₄ O₂ (percent): C, 56.40; H, 6.02; N,23.92. Found (percent): C, 56.52; H, 6.14; N, 23.92. NMR (DMSO-d₆): 1.59(m, 6H); 3.37 (m, 4H); 5.61 (d, 1H, 3.0 Hz); 5.88 (d, 1H, 3.0 Hz); 7.15(bs, 2H).

(e) A mixture of5-amino-7-(1-piperidinyl)-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-2-one (3.4g., 0.014 mole) and 5.6 g. of potassium hydroxide in 85 ml. of absoluteethanol is refluxed for a period of 6 hr. and then concentrated underreduced vacuum to dryness. The residue thus obtained triturated withwater affords 1.5 g. (51% yield) of product having a melting point of280°-283° C. (dec.). Crystallization of this material from ethylacetate-ethanol affords analytically pure2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide, m.p. 277° C. (dec.)(corr.).

Analysis. Calcd. for C₁₀ H₁₆ N₄ O (percent): C, 57.67; H, 7.74; N,26.90. Found (percent): C, 57.53; H, 7.89; N, 26.70. NMR (DMSO-d₆): 1.53(m, 6H); 3.10 (m, 4H); 5.58 (s, 2H); 6.31 (bs, 4H).

(f) The concentrated reaction mixture obtained from reaction of4-chloro-2,6-bis-(ethoxycarbonylamino)pyridine 1-oxide and piperidine inExample 2(a) hydrolyzed with potassium hydroxide in ethanol according tothe procedure described in Example 1(b) provides2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide. Acidification of2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide in ethanol with ethanolichydrogen chloride affords 2,6-diamino-4-(1-piperidinyl)pyridine 1-oxidehydrochloride.

Substituting piperidine for morpholine in the procedure of Example 1(b)affords 2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide.

EXAMPLE 3 Pharmaceutical Compositions

The 2,6-diamino-4-tertiary-amino-pyridine 1-oxides characterized byFormula I are compounded with pharmacologicaly acceptable carriers toprovide compositions useful in the present invention. Typical of thepharmaceutical compositions are the following:

(a) Tablets. -- The 2,6-diamino-4-tertiary-amino-pyridine 1-oxides ofFormula I are compounded into tablets according to the followingexample.

    ______________________________________                                        Material                Amount                                                ______________________________________                                        2,6-diamino-4-(1-piperidinyl)pyridine                                         1-oxide                 50.0 g.                                               Magnesium stearate      1.3 g.                                                Corn starch             12.4 g.                                               Corn starch pregelatinized                                                                            1.3 g.                                                Lactose                 185.0 g.                                              ______________________________________                                    

The foregoing materials are blended in a twin-shell blender and thengranulated and pressed into tablets weighing 200 mg. each. Each tabletcontains 40 mg. of active ingredient. The tablet may be scored inquarters so that a dose of 10 mg. of active ingredient may beconveniently obtained.

(b) Capsules. -- The 2,6-diamino-4-tertiary-amino-pyridine 1-oxides arecompounded into capsules according to the proportions set forth in thefollowing example.

    ______________________________________                                        Material              Amount                                                  ______________________________________                                        Active ingredient     25.0 mg.                                                Lactose               246.0 mg.                                               Magnesium stearate    4.0 mg.                                                 ______________________________________                                    

The foregoing materials are blended in a twin-shell blender and thenfilled into #1 hard gelatin capsules. Each capsule contains 25 mg. ofactive ingredient.

What is claimed is:
 1. A compound having the formula ##STR5## or apharmaceutically acceptable acid addition salt thereof wherein R isselected from the group consisting of morpholino, thiomorpholino, andN-methylpiperazino.
 2. The compound of claim 1 which is2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide.
 3. The compound of claim1 which is 2,6-diamino-4-(4-methyl-1piperazinyl)pyridine 1-oxide.